1. Field of the Invention
This invention relates to the use of a certain group of bisphosphonates for the regeneration of bone tissue and/or elimination of late complications subsequent to bone surgery. More particularly, the invention concerns the use of clodronate to enhance bone tissue formation after surgical replacement of endo-osteal material such as implantations, particularly dental implantations, and transplantations.
2. Description of the Prior Art
Bisphosphonates are synthetic organic compounds structurally related to pyrophosphate in that the pyrophosphate P-O-P-bond is replaced by a P-C-P-bond. In contrast to pyrophosphate, bisphosphonates are resistent to enzymatic hydrolysis in osseous tissue. The bisphosphonates are potent inhibitors of bone resorption and they have been successfully used in the treatment of hypercalcemia caused by various reasons. A great number of bisphosphonates have been studied, but only clodronate, etidronate and pamidronate have reached wider clinical use.
The main effect of the bisphosphonates is their ability to inhibit bone resorption, but contrary to the effect on mineralization, the mechanism involved is cellular (Fleisch H., Drugs 1991; 42: 919-44). These different effects vary greatly according to the structure of the individual bisphosphonate compound. The half-life of circulating bisphosphonates is very short, in the order of minutes to hours. Of a given dose, 20 to 50% is taken up by the skeleton, the rest being excreted in the urine. The half-life in bone is far longer and depends upon the turnover rate of the skeleton itself.
A review (Mian M. et al., Int J Clin Pharmacol Res. 1991; 11: 107-14) of 126 publications on clinical studies concerning the use of clodronate in the therapy of bone disease, involving 1930 patients, in order to evaluate the tolerability and the effects following short- and long-term administration of this drug, indicates that clodronate therapy does not have any clinically significant side-effects and confirm its tolerability and safety.
Of the many compounds belonging to the bisphosphonate family, clodronate has been widely used in hypercalcemia and osteolysis of malignancy (Bonjour J. P. and Rizzoli R., Calcif Tissue Int 1990; 46 Suppl: 20-25). All published reports indicate that clodronate can normalize plasma calcium in the majority of hypercalcemic, rehydrated cancer patients in whom increased bone resorption is the prevailing disturbed calcium flux (Fleisch H., Drugs 1991; 42: 919-44).
Various phosphonate compounds are also reported in the patent literature as being useful in the treatment of anomalous mobilization and deposition of calcium phosphate salts (bone mineral) in mammals. Reference is made to U.S. Pat. Nos. 3,678,164; 3,662,066; 3,553,314; 3,553,315; 3,584,124; 3,584,125 and 3,641,246. U.S. Pat. No. 3,683,080 discloses the use of clodronate and various other phosphonates for the treatment of anomalous calcification involving soft tissues and arthritic conditions. U.S. Pat. No. 4,234,645 discloses clodronate as useful in the treatment of various collagen diseases.
As discussed above, bisphosphonates are well documented with respect to their ability to inhibit bone resorption in connection with various diseases. The use of these compounds to promote bone tissue formation subsequent to surgical operations relating to endo-osteal prosthesis such as hip prostheses, plates used in internal rigid fixation and various kinds of implantations; osteomyelitis after decorticalization of necrotics from the mandible or bone transplantations has, however, never been suggested. Particularly in dental implantation surgery, patients with severe atrophy of the mandibular alveolar process are difficult to treat by conventional implant techniques. At the abutment connection operation mobile fixtures are found frequently. About half of the number of recorded failures occurred under the healing period (Adell R. et al., Int J Oral & Maxillofac Surg 1990, 5: 347-359). Autogenous bone grafts used for severely resorbed ridge augmentation usually resorb to a considerable extent (Baker R. D. et al., J Oral Surg 1970; 37: 486-89).